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Updated: Jul 18, 2025
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Study on the allosteric activation mechanism of SHP2 via elastic network models and neural relational inference
Ling Liu1,2, Yan Cheng3, Zhigang Zhang2
1Department of Thoracic Oncology, Affiliated Cancer Hospital, Guizhou Medical University, Guiyang, China. ouyangww73@163.com.
Abstract:
As a ubiquitous protein tyrosine phosphatase, SHP2 is involved in PD-1/PD-L1 mediated tumor immune escape and undergoes substantial conformational changes. Therefore, it is considered an ideal target for tumor intervention. However, the allosteric mechanisms of SHP2 binding PD-1 intracellular ITIM/ITSM phosphopeptides remain unclear, which greatly hinders the development of novel structure-based anticancer allosteric inhibitors. In this work, the open and closed structural models of SHP2 are first constructed based on this knowledge; next their motion modes are investigated via elastic network models such as the Gaussian network model (GNM), anisotropic network model (ANM) and adaptive anisotropic network model (aANM); and finally, a possible allosteric signaling pathway is proposed using a neural relational inference molecular dynamics (NRI-MD) simulation embedded with an artificial intelligence (AI) strategy. In GNM and ANM, the N-SH2, C-SH2 and PTP domains all exhibit distinct dynamics partitions, and the N-SH2/C-SH2 regions show a rigid rotation relative to PTP. According to a series of intermediate snapshots given by aANM, N-SH2 is first identified with pY223 specifically, inducing a D'E-loop to change from β-sheets to random coils, and then, C-SH2 serves as a fulcrum to drive N-SH2 to rotate 110° completely away from the original active sites of PTP. Finally, a possible allosteric signaling-transfer path for SHP2, namely R220-R138-T108-R32, is proposed based on NRI-MD sampling. This work provides a possible allosteric mechanism of SHP2, which is helpful for the following design of novel allosteric inhibitors and is expected to be used in clinical synergies with PD-1 monoclonal antibody.
Insights
This study reveals the allosteric mechanism of SHP2 phosphatase in cancer immune escape. Understanding this SHP2 pathway aids in designing new cancer inhibitors for combination therapy with PD-1 antibodies.
Area of Science:
- Biochemistry and Structural Biology
- Computational Biology and Bioinformatics
- Cancer Immunology
Background:
- SHP2 (PTPN11) is a protein tyrosine phosphatase crucial for PD-1/PD-L1 mediated tumor immune escape.
- SHP2 undergoes significant conformational changes, making it an attractive target for cancer therapy.
- The precise allosteric mechanisms of SHP2 binding to PD-1 phosphopeptides are not fully understood, hindering structure-based inhibitor development.
Purpose of the Study:
- To elucidate the allosteric mechanisms of SHP2 in response to PD-1 intracellular phosphopeptide binding.
- To identify potential allosteric signaling pathways within SHP2.
- To provide a structural basis for designing novel allosteric inhibitors targeting SHP2 for cancer treatment.
Main Methods:
- Construction of open and closed structural models of SHP2.
- Investigation of protein dynamics using elastic network models: Gaussian Network Model (GNM), Anisotropic Network Model (ANM), and adaptive ANM (aANM).
- Allosteric signaling pathway analysis using neural relational inference molecular dynamics (NRI-MD) simulations with artificial intelligence (AI).
Main Results:
- Distinct dynamic partitions were observed in the N-SH2, C-SH2, and PTP domains, with N-SH2/C-SH2 regions rotating rigidly relative to PTP.
- Specific binding of pY223 to N-SH2 induced a conformational change in the D'E-loop.
- The C-SH2 domain acted as a fulcrum, facilitating a 110° rotation of N-SH2 away from the PTP active site.
- A potential allosteric signaling pathway (R220-R138-T108-R32) was identified via NRI-MD.
Conclusions:
- A plausible allosteric mechanism for SHP2 in response to PD-1 phosphopeptide binding has been proposed.
- The findings provide critical insights for the rational design of novel SHP2-targeting allosteric inhibitors.
- This research is expected to facilitate clinical synergy between SHP2 inhibitors and PD-1 monoclonal antibodies in cancer therapy.
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